Prostate Cancer: Cholesterol-metabolism as a New Treatment Approach

03/06/2014
Photo: Image

This image shows liver metastasis of human prostate cancer, taken using a technique called stimulated Raman scattering microscopy. The bright dots represent intracellular lipid droplets enriched in cholesteryl ester;
© Purdue University

Researchers have discovered a link between prostate cancer aggressiveness and a compound called cholesteryl ester accumulated in lipid droplets inside single cancer cells, findings that could bring new diagnostic and treatment methods.

Findings also suggest that a class of drugs previously developed to treat atherosclerosis might be repurposed for treatment of advanced prostate cancer.

The research showed depletion of the compound cholesteryl ester significantly reduced prostate cancer cell proliferation, impaired its ability to invade a laboratory tissue culture and suppressed tumor growth in mice. "Our study provides an avenue towards diagnosis of aggressive prostate cancer. Moreover, we showed that depleting cholesteryl ester significantly impairs prostate cancer aggressiveness," said Ji-Xin Cheng of Purdue University's Weldon School of Biomedical Engineering and Department of Chemistry.

The research involved analysis of clinical samples harvested from prostate cancer patients, specialized cell lines and mice.

"Prostate cancer is the second-leading cause of cancer-related mortality in American men. Our finding offers a biological foundation that supports the beneficial effect of cholesterol-lowering drugs. Second, our study heralds the potential of using cholesteryl ester as a therapeutic target for advanced prostate cancer," said study co-author Timothy Ratliff. "These results together suggest that cholesteryl ester accumulation might be used for more accurate prediction of prostate cancer aggressiveness, if validated through further examination of a large number of tissue biopsies and correlation assessment of cholesteryl ester levels and clinical outcomes of patients."

A critical focus of the research is the analysis of individual lipid droplets inside single cells. Purdue researchers have developed an analytical tool called Raman spectromicroscopy that allows compositional analysis of single lipid droplets in living cells and mice.

"It is conceivable that cancer cells require reservoirs for lipids, namely lipid droplets. However, our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases," Cheng said.

The researchers learned that cholesteryl ester accumulation, which occurs only in advanced prostate cancer and its metastasis, results from the loss of a tumor-suppressing gene called PTEN and the activation of an intracellular metabolic pathway promoting tumor growth.

Findings show the drugs avasimibe and Sandoz 58-035 reduced the accumulation of cholesteryl ester and significantly hindered advanced prostate cancer growth in laboratory cell cultures and xenograft mouse models. These drugs did not show toxicity to animals.

"We note that avasimibe, Sandoz 58-035 and a class of similar drugs were developed to treat atherosclerosis, but the clinical trials were halted due to the lack of effectiveness in reducing plaque size," Cheng said. "The present study highlights a novel use of these drugs to treat advanced prostate cancer."

MEDICA.de; Source: Purdue University